This invention relates to a combination therapy for selected sex steroid dependent cancers in susceptible warm-blooded animals including humans comprising administering to such animals whose hormone output of their testes or ovaries, respectively, is blocked a therapeutically effective amount of an antiandrogen and/or an antiestrogen and/or at least one inhibitor of sex steroid biosynthesis, or pharmaceutical compositions thereof, wherein the selected sex steroid dependent cancers are testicular cancer, ovarian cancer, colon-rectal cancer, renal cancer, pancreatic cancer, liver cancer, stomach cancer, skin cancer, uterine cancer, brain cancer or larynx cancer. The hormone output of the animal's testes or ovaries, respectively, can be blocked by surgical or chemical means. (In post-menopausal women the attending clinician may decide that the hormone output of the ovaries need not be blocked.)
U.S. patent application Ser. No. 638,883 relates to the treatment of female breast cancer by use of a combination therapy comprising administering an antiandrogen and an antiestrogen to female after the hormone output of her ovaries has blocked by chemical or surgical means.
U.S. patent application Ser. No. 699,702 relates to the treatment of female breast cancer by use of a therapy comprising administering to a female after the hormone output of her ovaries has been blocked by chemical or surgical means an antiandrogen and optionally an inhibitor of sex steroid biosynthesis.
U.S. patent application Ser. No. 699,710 relates to a treatment of male breast cancer by using a therapy comprising administering to a male after the hormone output of his testes has been blocked by chemical or surgical means an antiandrogen and optionally at least one inhibitor of sex steroid biosynthesis.
U.S. patent application Ser. No. 699,711 relates to a treatment of prostate cancer by use of a combination therapy comprising administering an antiandrogen and at least one inhibitor of sex steroid biosynthesis to a male after the hormone output of his testes has been blocked by chemical or surcical means.
While various investigators have been studying hormone-dependent breast and prostate cancer, none have proposed the combination therapy of this invention.
A. V. Schally et al., Cancer Treatment Reports, 68, (No. 1) 281-289 (1984), summarize the results of animal and clinical studies on growth inhibition of hormone-dependent mammary and prostate tumors by use of analogues of luteinizing hormone-releasing hormones, the so-called LH-RH agonists and suggest that LH-RH analogs and/or antagonists may have potential for treating breast cancer.
T. W. Redding and A. V. Schally, Pro. Natl. Acad. Sci. USA, 80, 1459-1462 (1983), disclose reduction of estrogen-dependent mammary tumors in rats and mice by use of an LH-RH agonist, [D-Trp.sup.6 ]LH-RH or of two specific antagonists and inhibition of prostate tumor growth in rats of chronic use of an LH-RH agonist, [D-Trp.sup.6 ]LH-RH.
In U.S. Pat. No. 4,071,622, it is disclosed that use of certain LH-RH agonists causes regression of DMBA-induced mammary carcinoma in rats.
In U.S. Pat. No. 4,472,382, it is disclosed that prostate adenocarcinoma, benign prostate hypertrophy and hormone-dependent mammary tumors may be treated with various LH-RH agonists and that prostate adenocarcinoma and benign hypertrophy may be treated by use of various LH-RH agonists and an antiandrogen. However, there is no suggestion or disclosure of the present invention.
Some clinical improvement in premenopausal women with breast cancer by use of the two LH-RH agonists, Buserelin and Leuprolide, is also reported by H. A. Harvey et al. "LH-RH analogs in the treatment of human breast cancer", LH-RH and its Analogs--A New Class of Contraceptive and Therapeutic Agents (B. H. Vickery and J. J. Nestor, Jr., and E. S. E. Hafez, eds) Lancester, MTP Press, (1984) and by J. G. M. Klijn et al. "Treatment with luteinizing hormone releasing hormone analogue (Buserelin) in premenopausal patients with metastatic breast cancer", Lancet, 1, 1213-1216 (1982).
Treatment of advanced breast cancer with aminoglutethimide after therapy with the antiestrogen, Tamoxifen is disclosed by A. V. Buzdar et al., Cancer, 50, 1708-1712 (1982).
H. Flax et al., Lancet, 1204-1207, (1973), suggest some women's breast cancers are androgen-dependent.
In U.S. Pat. No. 4,329,364, it is disclosed that the antiandrogen, 4'-nitro-3'-trifourormethyl isobutyranilide may be used for treatment of prostatic cancer.
Some clinical improvement in men with prostate cancer by use of the two LH-RH agonists, Buserelin and Leuprolide, is also reported by N. Faure et al. at pages 337-350 and by R. J. Santen et al. at pages 351-364, respectively, LH-RH and its Analogs--A New Class of Contraceptive and Therapeutic Acents (B. H. Vickery and J. J. Nestor, Jr., and E. S. E. Hafez, eds) Lancester, MTP Press, (1984).
R. Santen et al., The Journal of Steroid Biochemistry, Volume 20, No 6B, at page 1375 (1984), disclose that use of ketoconazole in combination with chronic administration of Leuprolide in rodents decreased basal and Leuprolide stimulated testosterone levels.
D. Kerle et al., The Journal of Steroid Biochemistry, Volume 20, No 6B, at page 1395 (1984) disclose that the combined use of a LH-RH analogue and ketoconazole produced objective responses in some prostate cancer patients who have relapsed or failed to respond to treatment with a LH-RH analogue alone.
F. Labrie et al., Abstracts of 7th International Congress of Endrocrinology, Excerpta Medica (1984) at page 98 discloses that treatment of prostate cancer patients with LH-RH agonists alone causes a transient increase in serum androgen levels lasting for 5 to 15 days before castration levels are reached.
F. Labrie et al., The Prostate, 4, 579-594 (1983), disclose that use of a combination therapy of an LH-RH agonist (Buserelin) and an antiandrogen (Anandron) to treat advanced prostate cancer in previously untreated patients effects simultaneous inhibition of androgens of both testicular and adrenal origin.
F. Labrie et al., J. Steroid Biochem., 19, 99-1007 (1983), disclose the treatment of prostate cancer by the combined administration of an LH-RH agonist and an antiandrogen. Labrie et al. disclose animal and clinical data in support of the proposition that the combined LH-RH/antiandrogen treatment neutralizes the stimulatory influence of all androgens on the development and growth of androgen-dependent prostatic cancer.
In U.S. Pat. No. 4,094,994, it is disclosed that the use of antiestrogens such as meso-3,4-bis(3'-hydroxyphenyl)hexane inhibits MCF7 human breast tumor cells. In fact, the inhibitory activity of the antiestrogen was antagonized by estradiol.
H. Mouridsen et al., Cancer Treatment Review 5, 131-141, (1978), disclose that Tamoxifen, an antiestrogen is effective in remission of advanced breast cancer in about 30% of the patients treated.
J. G. M. Klijn et al., (J. Steroid Biochem, Vol. 20 (No. 6B), 1381 (1984), disclosed the combined use of the antiestrogen, Tamoxifen, and the LH-RH agonist, Buserelin, for treatment of breast cancer is known, but objective remission of such cancers remains low (35%).